Growth hormone (somatotropin) (GH) is a 22 kDa protein that is synthesized in and secreted by the anterior pituitary. Kopchick et al., 2002, Endocrine Reviews, 23(5):623-646. GH functions as a central endocrine regulator of growth both by acting directly on tissues and stimulating the release of insulin-like growth factor-1 (IGF-1) by the liver and other tissues. Okada et al., 2001, Trends in Molecular Medicine 7(3):126-132. In turn, IGF-1 acts on tissues to stimulate body growth.
GH signals through the growth hormone receptor (GHR), a single pass transmembrane protein with no intrinsic tyrosine kinase activity. The growth hormone receptor (GHR) is a class 1 cytokine receptor. Waters et al., 2006, Journal of Molecular Endocrinology, 36, 1-7. GHR signalling involves the role of at least three major pathways, STATs, MAPK, and PI3-kinase/Akt. The current understanding of GHR signaling is that GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Brown, R. J. et al., 2005, Nature Struct. Mol. Biol. 12:814-821. At present, the mechanism by which GH binding converts the inactive predimerized GHR to its active signaling conformation is uncertain. Yang et al., 2008, Mol. Endocrinol 22(4):978-988. The interaction of GH with dimerized GHR is mediated by two asymmetric binding sites on GH, each with distinct affinity. Yang et al., 2008.
GHRs are ubiquitously distributed. While originally identified in hepatic tissue, they are known to be present in liver, bone, kidney, adipose, muscle, eye, brain, and heart, as well as in immune tissues like B cells, lymphocytes, spleen, and thymus. GHR antagonists, such as Pegvisomant (SOMAVERT®), have been developed for use as drugs to treat, for example, acromegaly (Kopchick et al., 2002).
Abnormally high GH levels have been associated with a number of disorders. The two classic disorders which are directly caused by high levels of GH are acromegaly and gigantism. Changes associated with acromegaly include coarsening of body hair, thickening and darkening of the skin, enlargement and overactivity of sebaceous and sweat glands such that patients frequently complain of excessive perspiration and offensive body odor, overgrowth of the mandible, cartilaginous proliferation of the larynx causing a deepening of the voice, and enlargement of the tongue. In addition, excess GH in these patients is responsible for proliferation of articular cartilage which may undergo necrosis and erosion and endoneural fibrous proliferation which causes peripheral neuropathies. Excess GH also increases tubular reabsorption of phosphate and leads to mild hyperphosphatemia. Many of these symptoms are also seen in patients with gigantism.
Current treatments for acromegaly and gigantism typically aim to lower IGF-1 levels in plasma and/or tissue through either destruction of the pituitary or drug treatment. The role of IGF-1 in GH-mediated disorders, such as acromegaly and gigantism is well recognized. Melmed et al., 1994, Amer. J. Med. 97:468-473.
Current treatment for acromegaly and gigantism include pituitary ablation, radiation treatment, bromocriptine mesylate, somatostatin analogs, and Pegvisomant. Pituitary ablation is a surgical procedure and, like any surgical procedure, is associated with a significant risk of complications including mortality. There are also risks associated with radiation treatment of the pituitary as well. In addition, the efficacy of radiation treatment may be delayed for several years. Moreover, these treatment modalities are not specific against that part of the pituitary that produces GH and may adversely affect adjacent tissue as well. Bromocriptine mesylate is a dopamine like drug which suppresses the production of GH. Recently, octreotide, a long-acting somatostatin analog has also been used to treat patients with acromegaly and gigantism which is refractory to surgery, radiation, and/or bromocriptine mesylate. Somatostatin analogs inhibit insulin secretion and long-term and are associated with increase risk of insulin resistance, impaired insulin secretion, and diabetes. Baldelli et al., 2003, Clin. Endocrinol. (Oxf). 59(4):492-499. Pegvisomant is a GH antagonist comprising a recombinantly produced PEGylated human GH analog. Treatment with pegvisomant currently involves daily dosing subcutaneously.
Although anti-human GHR antibodies have been described, it has been difficult to identify monoclonal antibodies that specifically bind to both human and non-human primate GHR, are high affinity, have high specificity, and have potent antagonizing activity.